CDK-inhibiting pyrrolopyrimidine carboxamide derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition containing the same as active ingredient for preventing or treating hepatocellular carcinoma

Abstract

The present invention relates to a CDK-inhibiting pyrrolopyrimidine carboxamide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient for preventing or treating liver cell cancer. Compositions comprising a pyrrolopyrimidine carboxamide derivative of the present invention suppress the cell growth of SNU-354 cell, which is a liver cancer stem cell in humans, by inhibiting CDK1 and CDK2, and induces cell apoptosis of the cell by inhibiting CDK7 and CDK 7. Such compositions are useful for preventing or treating liver cell cancer.

What is claimed is: 
     
       1. A pyrrolopyrimidine carboxamide derivative represented by the following formula 1, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein in the Formula 1, 
         R 1  is hydrogen or R 3 C(═O); 
         R 3  is C 1 -C 6  straight or branched alkyl, C 3 -C 8  cycloalkyl or phenyl; and 
         R 2  is hydrogen or acetyl. 
       
     
     
       2. The pyrrolopyrimidine carboxamide derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the R 3  is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl, cyclohexyl or phenyl. 
     
     
       3. The pyrrolopyrimidine carboxamide derivative or the pharmaceutically acceptable salt thereof according to  claim 1 , wherein the compound represented by formula 1 is selected from the group consisting of the following compound (1)-compound (7):
 (1) 4-amino-6-bromo-1-((2S,3R,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; 
 (2) ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl isobutyrate; 
 (3) ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl pivalate; 
 (4) (2S,3R,4S,5S)-2-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-5-(isobutyryloxy methyl)-tetrahydrofuran-3,4-diyl diacetate; 
 (5) ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl benzoate; 
 (6) ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl propionate; and 
 (7) ((2S,3R,4R,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo[2,3-d]pyrimidine-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl)methyl cyclohexanecarboxylate. 
 
     
     
       4. A method for preparing the pyrrolopyrimidine carboxamide derivative of  claim 1  comprising the following steps as shown in the following Reaction Scheme 1:
 preparing the compound of formula 4 by reacting the compound of formula 2 with the compound of formula 3 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) after adding N,O-bis(trimethylsilyl) acetamide (BSA) to the compound of formula 2 (step 1); 
 preparing the compound of formula 5 by adding ammonium hydroxide solution to the compound of formula 4 (step 2); and 
 preparing the compound of formula 1a by adding hydrogen peroxide to the compound of formula 5 (step 3): 
 
       
         
           
           
               
               
           
         
       
     
     
       5. The method for preparing the pyrrolopyrimidine carboxamide derivative according to  claim 4 , further comprising an additional step of preparing the compound of formula 1b′ from the compound of formula 1a via esterification as shown in the following Reaction Scheme 2: 
       
         
           
           
               
               
           
         
         wherein in Reaction Scheme 2, 
         R 1  is R 3 C(═O); and 
         R 3  is C 1 -C 6  straight or branched alkyl, C 3 -C 8  cycloalkyl or phenyl; and wherein 1a is contacted with a carboxylic acid anhydride. 
       
     
     
       6. The method for preparing the pyrrolopyrimidine carboxamide derivative according to  claim 4 , further comprising wherein the compound of formula 2, which is the starting material, is prepared by the following steps as shown in the following Reaction Scheme 3:
 preparing the compound of formula 7 by adding hydrogen bromide to the compound of formula 6, tetracyanoethylene, in the presence of acetone and ethylacetate (step 1); and 
 preparing the compound of formula 2 by adding triethyl orthoformate and ammonia water to the compound of formula 7 (step 2): 
 
       
         
           
           
               
               
           
         
       
     
     
       7. The method for preparing the pyrrolopyrimidine carboxamide derivative according to  claim 4 , further comprising wherein the compound of formula 3 is prepared according to Reaction Scheme 4 by reacting L-xylose of formula 8 with boric acid, to which acetic acid and acetic anhydride are added, followed by reaction at high temperature: 
       
         
           
           
               
               
           
         
       
     
     
       8. The method for preparing the pyrrolopyrimidine carboxamide derivative according to  claim 5 , further comprising an additional step of preparing the compound of formula 1d from the compound of formula 1b′ via esterification as shown in the following Reaction Scheme 5: 
       
         
           
           
               
               
           
         
       
       wherein in Reaction Scheme 5,
 R 1  is R 3 C(═O); and 
 R 3  is C 1 -C 6  straight or branched alkyl, C 3 -C 8  cycloalkyl or phenyl. 
 
     
     
       9. A method for treating hepatocellular carcinoma comprising administering a therapeutically effective dose of a pyrrolopyrimidine carboxamide derivative or a pharmaceutically acceptable salt thereof of  claim 1  to a subject having hepatocellular carcinoma. 
     
     
       10. The method for treating hepatocellular carcinoma according to  claim 9 , wherein a pyrrolopyrimidine carboxamide derivative or a pharmaceutically acceptable salt thereof has cyclin-dependent kinase (CdK) inhibiting activity. 
     
     
       11. The method for treating hepatocellular carcinoma according to  claim 10 , wherein the said Cdk includes Cdk1, Cdk2, Cdk7, and Cdk9.